PDB-7mu6: Ask1 bound to compound 28

ID or keywords:

Entry

Database: PDB / ID: 7mu6

Title

Ask1 bound to compound 28

Components

Mitogen-activated protein kinase kinase kinase 5

Keywords

TRANSFERASE/INHIBITOR / ASK1 / TRANSFERASE / TRANSFERASE-INHIBITOR complex

Function / homology

Function and homology information

cellular response to reactive nitrogen species / neuron intrinsic apoptotic signaling pathway in response to oxidative stress / IRE1-TRAF2-ASK1 complex / protein kinase complex / mitogen-activated protein kinase kinase kinase / programmed necrotic cell death / JUN kinase kinase kinase activity / endothelial cell apoptotic process / positive regulation of p38MAPK cascade / intrinsic apoptotic signaling pathway in response to oxidative stress ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.165 Å

Authors

Chodaparambil, J.V. / Marcotte, D.J.

Citation

Journal: J.Med.Chem. / Year: 2021
Title: Discovery of Potent, Selective, and Brain-Penetrant Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitors that Modulate Brain Inflammation In Vivo.
Authors: Jones, J.H. / Xin, Z. / Himmelbauer, M. / Dechantsreiter, M. / Enyedy, I. / Hedde, J. / Fang, T. / Coomaraswamy, J. / King, K.W. / Murugan, P. / Santoro, J.C. / Hesson, T. / Walther, D.M. / ...

History

Deposition	May 14, 2021	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Jul 17, 2024	Provider: repository / Type: Initial release

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	7mu6.cif.gz	227.8 KB	Display	PDBx/mmCIF format
PDB format	pdb7mu6.ent.gz		Display	PDB format
PDBx/mmJSON format	7mu6.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Summary document	7mu6_validation.pdf.gz	1.1 MB	Display	wwPDB validaton report
Full document	7mu6_full_validation.pdf.gz	1.1 MB	Display
Data in XML	7mu6_validation.xml.gz	22.8 KB	Display
Data in CIF	7mu6_validation.cif.gz	32.7 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/mu/7mu6 ftp://data.pdbj.org/pub/pdb/validation_reports/mu/7mu6	HTTPS FTP

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Related structure data

Related structure data	4bf2S S: Starting model for refinement
Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI

Deposited unit

A: Mitogen-activated protein kinase kinase kinase 5

B: Mitogen-activated protein kinase kinase kinase 5

hetero molecules

75.8 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

A: Mitogen-activated protein kinase kinase kinase 5

hetero molecules

defined by author
Evidence: gel filtration
37.9 kDa, 1 polymers

2

B: Mitogen-activated protein kinase kinase kinase 5

hetero molecules

defined by author
37.9 kDa, 1 polymers

Unit cell

Length a, b, c (Å)	77.906, 77.906, 425.737
Angle α, β, γ (deg.)	90.00, 90.00, 120.00
Int Tables number	179
Space group name H-M	P6₅22

Components on special symmetry positions

ID	Model	Components
1	1	A-1225- HOH
2	1	B-1191- HOH

#1: Protein	Mitogen-activated protein kinase kinase kinase 5 / Apoptosis signal-regulating kinase 1 / ASK-1 / MAPK/ERK kinase kinase 5 / MEK kinase 5 / MEKK 5 Mass: 37518.453 Da / Num. of mol.: 2 / Fragment: kinase domain Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: MAP3K5, ASK1, MAPKKK5, MEKK5 / Production host: Escherichia coli (E. coli) References: UniProt: Q99683, mitogen-activated protein kinase kinase kinase
#2: Chemical	ChemComp-A1AWT / 2-methoxy-N-(6-{4-[(2S)-1,1,1-trifluoropropan-2-yl]-4H-1,2,4-triazol-3-yl}pyridin-2-yl)pyridine-3-carboxamide Mass: 392.335 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₁₇H₁₅F₃N₆O₂ / Feature type: SUBJECT OF INVESTIGATION
#3: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 267 / Source method: isolated from a natural source / Formula: H₂O
Has ligand of interest	Y

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 2.49 Å³/Da / Density % sol: 50.51 %
Crystal grow	Temperature: 294 K / Method: vapor diffusion, sitting drop Details: 0.1M BisTRIS pH 5.5, 0.2M ammonium acetate, 3% sorbitol and 12% PEG3350

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Data collection

Diffraction	Mean temperature: 93 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97 Å
Detector	Type: MAR CCD 165 mm / Detector: CCD / Date: Nov 10, 2017
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.97 Å / Relative weight: 1
Reflection	Resolution: 2.16→30 Å / Num. obs: 42487 / % possible obs: 99 % / Redundancy: 15.8 % / CC_1/2: 0.99 / R_merge(I) obs: 0.15 / Net I/σ(I): 12.9
Reflection shell	Resolution: 2.16→2.28 Å / Num. unique obs: 6014 / CC_1/2: 0.99

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Processing

Software

Name	Version	Classification
PHENIX	1.11.1_2575	refinement
XDS		data reduction
Aimless		data scaling
PHENIX		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 4bf2

4bf2

Resolution: 2.165→29.5 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.43 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.2144	2106	4.98 %
R_work	0.1895	-	-
obs	0.1908	42328	99.98 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL

Refinement step

Cycle: LAST / Resolution: 2.165→29.5 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	4018	0	56	267	4341

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.004	4168
X-RAY DIFFRACTION	f_angle_d	0.819	5642
X-RAY DIFFRACTION	f_dihedral_angle_d	5.086	2498
X-RAY DIFFRACTION	f_chiral_restr	0.055	607
X-RAY DIFFRACTION	f_plane_restr	0.009	728

LS refinement shell

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	Refine-ID	% reflection obs (%)
2.165-2.2149	0.2993	122	0.2532	2605	X-RAY DIFFRACTION	100
2.2149-2.2703	0.2651	156	0.2244	2577	X-RAY DIFFRACTION	100
2.2703-2.3316	0.207	132	0.1999	2615	X-RAY DIFFRACTION	100
2.3316-2.4002	0.2124	127	0.1899	2628	X-RAY DIFFRACTION	100
2.4002-2.4776	0.2127	132	0.1911	2634	X-RAY DIFFRACTION	100
2.4776-2.5661	0.2031	152	0.1878	2607	X-RAY DIFFRACTION	100
2.5661-2.6688	0.2137	134	0.1949	2656	X-RAY DIFFRACTION	100
2.6688-2.7902	0.2191	137	0.1932	2667	X-RAY DIFFRACTION	100
2.7902-2.9372	0.2542	142	0.2001	2635	X-RAY DIFFRACTION	100
2.9372-3.121	0.2425	146	0.1946	2682	X-RAY DIFFRACTION	100
3.121-3.3617	0.2187	134	0.1969	2681	X-RAY DIFFRACTION	100
3.3617-3.6994	0.1841	129	0.1805	2720	X-RAY DIFFRACTION	100
3.6994-4.2334	0.2123	145	0.1663	2723	X-RAY DIFFRACTION	100
4.2334-5.3284	0.168	138	0.1633	2799	X-RAY DIFFRACTION	100
5.3284-29.5	0.2307	180	0.2088	2993	X-RAY DIFFRACTION	100

Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

ID	L11 (°²)	L12 (°²)	L13 (°²)	L22 (°²)	L23 (°²)	L33 (°²)	S11 (Å °)	S12 (Å °)	S13 (Å °)	S21 (Å °)	S22 (Å °)	S23 (Å °)	S31 (Å °)	S32 (Å °)	S33 (Å °)	T11 (Å²)	T12 (Å²)	T13 (Å²)	T22 (Å²)	T23 (Å²)	T33 (Å²)	Origin x (Å)	Origin y (Å)	Origin z (Å)
1	6.7485	3.7622	0.0851	4.9788	0.0436	3.3978	-0.0226	0.1515	-0.3818	-0.0049	-0.0131	-0.1984	0.014	0.0716	0.022	0.347	0.1279	-0.0377	0.2978	0.0008	0.2633	10.7069	0.502	-20.4921
2	2.1815	1.2108	0.2391	1.5375	-0.1991	2.1012	-0.1517	-0.3665	-0.0964	0.1681	0.1815	-0.0667	-0.0043	0.2798	-0.0735	0.3467	0.1389	0.0035	0.2146	0.0193	0.1923	2.4759	1.6863	-20.5887
3	4.7733	-0.4436	-0.7298	3.2298	1.2403	4.4589	0.0623	-0.8056	0.0635	0.8013	0.1981	0.0906	0.0494	-0.1634	-0.1191	0.4919	0.1299	0.0729	0.3284	0.0764	0.2576	-5.248	2.5293	-13.5217
4	2.9097	-0.198	0.9207	1.9833	-0.1769	2.5685	0.2231	-0.5497	-0.4373	0.134	-0.0281	0.1237	0.5781	-0.1328	-0.0618	0.423	0.0999	0.075	0.2071	0.0405	0.2844	-5.0437	-1.0192	-19.3946
5	3.4744	-0.6804	0.9741	4.4517	-2.1417	4.9905	0.3506	0.1805	0.2682	-0.4213	-0.5422	-0.2485	-0.3241	0.7079	0.1195	0.321	0.1351	0.0698	0.1591	-0.0111	0.2447	-4.2956	16.6078	-37.5717
6	2.7989	-1.2822	-0.2634	2.4263	-0.3141	1.8437	0.0207	-0.1544	-0.1997	-0.0966	0.0457	0.392	0.2564	-0.0267	-0.0963	0.2674	0.055	0.0308	0.1403	0.0008	0.28	-14.4773	8.4708	-30.1462
7	3.7125	3.0144	-0.1758	2.9177	-0.4139	0.1143	-0.0756	-1.0721	0.4676	1.1909	0.2973	0.2681	0.001	-0.251	-0.095	0.4903	0.1695	0.1039	0.4631	-0.0057	0.2938	-14.4086	12.2826	-15.5395
8	1.2946	0.8809	-0.8906	1.0934	-1.5261	2.3728	-0.1103	-0.7447	-0.4347	0.6297	-0.082	0.3441	-0.6292	-0.2088	0.0753	0.4909	0.2615	0.0894	0.4684	-0.0196	0.3678	-19.5291	22.52	-16.9755
9	1.8122	-0.7193	0.234	3.3988	-0.3813	2.7324	-0.1234	-0.1551	0.0276	0.0581	0.0911	0.361	-0.3413	-0.3409	0.0612	0.2941	0.1525	0.0287	0.2166	-0.022	0.3017	-19.1266	23.0828	-30.6312
10	2.4579	-0.3542	-1.3954	2.5763	0.2507	3.0771	-0.0238	0.0159	-0.3825	-0.133	0.0406	0.0227	-0.0124	0.1529	0.0647	0.4534	0.0833	-0.0598	0.3001	-0.0452	0.2641	-57.5596	1.9256	-14.7712
11	3.0238	-1.2584	0.3891	2.6172	0.2305	2.1722	0.1294	0.1985	0.0783	-0.6002	-0.1137	0.5061	-0.5356	0.0229	-0.0232	0.4862	-0.0015	0.0061	0.2716	-0.0433	0.2521	-51.28	6.9385	-12.5066
12	3.2476	-0.0715	0.0943	5.4234	-1.6646	2.5557	0.0291	0.4868	0.5078	-1.3586	0.1543	-0.0677	-1.0668	0.4843	-0.2362	0.9784	-0.1218	0.0716	0.3768	-0.0123	0.2979	-46.5525	16.3896	-16.9786
13	3.2095	-0.4907	-0.145	3.3624	-0.2273	2.7255	0.0211	0.4639	0.1045	-0.8275	0.1505	-0.1371	-0.0779	0.139	-0.1664	0.5011	-0.0533	0.0918	0.2614	-0.0633	0.2994	-43.6472	9.8406	-12.9976
14	3.5457	0.3006	0.1951	3.8663	1.5555	7.8752	0.1175	-0.194	0.1406	0.3426	-0.2691	0.4399	0.2245	-0.5014	0.0595	0.3461	-0.0391	0.0941	0.2486	-0.061	0.3293	-52.7961	12.7855	10.354
15	1.4235	1.0972	-0.113	3.3447	0.9257	3.1647	0.0992	-0.0266	0.1532	-0.1425	0.0812	-0.4058	-0.2295	0.3813	-0.1654	0.3077	-0.0564	0.0584	0.2645	-0.0913	0.3297	-40.3382	15.8164	2.668
16	4.3086	2.2344	-0.5721	2.1795	-1.6043	1.6819	-0.2514	0.8427	0.3266	-1.2772	0.1719	-0.0594	-1.3909	-0.0475	-0.3016	0.8757	-0.1684	0.1669	0.2795	0.0103	0.3475	-41.6825	24.616	-8.3337
17	0.5805	0.8976	-1.2418	3.3412	-2.2334	2.6469	-0.1153	0.5439	0.5884	-0.8289	0.1335	-0.0997	-1.3343	-0.0758	0.1036	1.2391	-0.0882	0.0999	0.3979	-0.0007	0.5988	-44.6224	34.6317	-0.0876
18	1.2072	0.4905	-1.5557	4.5872	0.3005	4.9368	0.2031	-0.1113	0.2792	0.2608	0.0605	-0.2169	-1.1495	-0.049	-0.1875	0.6176	-0.0636	0.0619	0.3002	-0.1217	0.3922	-43.5551	27.9988	11.3452

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	chain 'A' and (resid 671 through 684 )
2	X-RAY DIFFRACTION	2	chain 'A' and (resid 685 through 703 )
3	X-RAY DIFFRACTION	3	chain 'A' and (resid 704 through 731 )
4	X-RAY DIFFRACTION	4	chain 'A' and (resid 732 through 758 )
5	X-RAY DIFFRACTION	5	chain 'A' and (resid 759 through 776 )
6	X-RAY DIFFRACTION	6	chain 'A' and (resid 777 through 820 )
7	X-RAY DIFFRACTION	7	chain 'A' and (resid 821 through 842 )
8	X-RAY DIFFRACTION	8	chain 'A' and (resid 843 through 859 )
9	X-RAY DIFFRACTION	9	chain 'A' and (resid 860 through 939 )
10	X-RAY DIFFRACTION	10	chain 'B' and (resid 671 through 684 )
11	X-RAY DIFFRACTION	11	chain 'B' and (resid 685 through 703 )
12	X-RAY DIFFRACTION	12	chain 'B' and (resid 704 through 731 )
13	X-RAY DIFFRACTION	13	chain 'B' and (resid 732 through 758 )
14	X-RAY DIFFRACTION	14	chain 'B' and (resid 759 through 776 )
15	X-RAY DIFFRACTION	15	chain 'B' and (resid 777 through 820 )
16	X-RAY DIFFRACTION	16	chain 'B' and (resid 821 through 842 )
17	X-RAY DIFFRACTION	17	chain 'B' and (resid 843 through 859 )
18	X-RAY DIFFRACTION	18	chain 'B' and (resid 860 through 940 )

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